Process of preparing sodium salts of



"mural"? Unite PROCESS OF PREPARING SODIUM SALTS OF SUBSTITUTED MALONICACIDS" No Drawing. Application June 10, 1957 Serial No. 664,455

9 Claims. (Cl. 260- -515) This invention relates to methods of preparingsodium salts of substituted malonic acids and more particularly to amethod of preparing, recovering and purifying disodium salts ofmonosubstituted malonic acids.

The sodium salts of substituted malonic acids are useful when added toor otherwise incorporated into smoking tobacco to provide, duringburning or smoking of the tobacco, certain desired flavor oraroma-producing acids. These flavoring acids are formed in situ by thedecarboxylation of the substituted malonic acid type compounds asdisclosed in United States Patent No. 2,766,- 145, issued October 19,1956, to Samuel OBrien Jones. As disclosed in that patent, the flavoringacids so released are volatile, monocarboxylicorganic acids having 3 to8 carbon atoms. Thus the substituent in the malonic acid type compoundis usually a hydrocarbon radical having from 1 to 6 carbon atoms. Thedisodium salts of monosubstituted malonic acids may be prepared bysaponification in an aqueous medium of the corresponding substitutedmalonic ester, which latter may be produced by variations of the wellknown malonic ester synthesis. In accordance with such prior arttechniques the monosubstituted malonic ester is saponified in an aqueoussolution with a base such as sodium hydroxide. The aqueous reactionmixture contains the desired disodium salt of the substituted malonicacid along with unreacted sodium hydroxide and ester, alcohol residuesfrom the saponification, and undesired side reaction products such assalts of unsubstituted malonic acid and the like. Inasmuch as thesesubstances are for the most part readily soluble in the aqueoussolution, the separation of the substituted malonic acid salt isrendered rather difficult and may be tedious. Accordingly, it is oneobject of the present invention to provide an improved method ofpreparing disodium salts of substituted malonic acids.

Another object is the provision of a process for recovering disodiumsalts of monosubstituted malonic acids in a substantially pure form.

Another object is the provision of a process for saponifying andrecovering in a relatively pure form, a disodium salt of amonosubstituted malonic acid in a single step without the necessity ofintermediate 'isolation and purification procedures.

These and other objects of the present invention will be seen from thefollowing specification and appended claims.

In one broad form the present invention comprises a process forpreparing and recovering relatively pure disodium salts of substitutedmalonic acids which comprises saponifying an ester of a monosubstitutedmalonic acid with an alkaline sodium compound in a solution of a loweralcohol and thereafter recovering from said reaction mixture thedisodium salt of the substituted malonic acid which is precipitatedtherein. Generally the substituted malonic esters to which the processof atet ice

- the present invention applicable may be characterized by the followingstructural formula:

' R -CH O 0 OR:

wherein R is a hydrocarbon radical containing up to 6 carbon atoms and Rand R are saturated aliphatic hydrocarbon radicals. In a preferredembodiment of the present invention R is a cyclic hydrocarbon radical orsaturated aliphatic hydrocarbon radical containing 2 to 4 carbon atoms.Particularly preferred substituents corresponding to R are isopropyl,sec-butyl and phenyl radicals. Generally R and R are alcohol residueswhich may be characterized as lower alkyl and as particularly preferredembodiments may be characterized as methyl or ethyl.

The alcohols usedin the saponification medium of the present inventionare the lower alcohols containing 1 to 3 carbon atoms.- Within thisgroup, alcohols which are most preferred are ethanol and methanol, andmixtures of these alcohols are also contemplated. The alkaline sodiumcompound useful in the present saponification process may be any sodiumcompound which upon hydrolysis is sufficiently alkaline to saponify thesubstituted malonic ester starting material. An example of such materialis sodium. hydroxide. Generally the amount of sodium hydroxide is notcritical except that sufficient quantities should be employed to insuresubstantially complete saponification of the malonic ester startingmaterial.

While the process of the present invention is preferably carried outunder substantially anhydrous conditions and using as the saponificationmedia substantially anhydrous alcohol, it is also true that the processmay be carried out using as a saponification medium an alcohol or ablend of alcohols in admixture with relatively small amounts of water.Relatively large amounts of water will result in solubilizing thedesired disodium salt of the substituted malonic acid. Accordingly, whena good yield is to be obtained the amount of water present, if any,should be less than 30% by weight and preferably less than 20% byweight.

The reaction may be carried out at various temperatures and it ispreferred that the reaction be carried out at an elevated temperaturesuch as for example the reflux temperature of the reaction mixture. Ifdesired, the reaction may be carried out under reflux at normalatmospheric pressure or pressures slightly above or below normalatmospheric pressure. The timerequired for saponification in thisprocess is not critical and varies with the concentration of thereactants and the temperature at which the process is carried out.Generally sufiicient time should be allowed to substantially completelyconvert the substituted malonic ester to the corresponding disodiumsalt. The extent of reaction may be determined by conventionalanalytical techniques. 7

In the process of this invention the substituted malonic ester isadmixed with an alcoholic sodium hydroxide solution. The reaction ispreferably carried out at reflux temperatures which may be continued fora period of time to insure complete reaction. During the course of thesaponification the disodium salt of the substituted malonic acid formedis precipitated. After saponification is complete, theprecipitateddisodium salt of the substituted malonic acid may be recovered from thereaction mixture by filtration, centrifuging, decantation, or likeprocedure. 7

The following examples will illustrate the preparation ofmonosubstituted ma1onic esters .and the .saponification and recovery ofthe disodium salts thereof, according to the process of the presentinvention.

EXAMPLE I Preparation, of isopropylmalonic ester Under anhydrousconditions a solution of 110 grams of sodium methylate in 340 grams ofmethanol is heated to reflux and 320.3 grams of vdiethyl malonate isadded, with stirring, during five minutes. Then 248.5 grams of isopropylbromide are added dnringfive rninutes and the mixtureis stirred andrefluxed for four hours. At the end of the reflux period the mixture isdisti led atreduced pressure forrernoval of alcohols and unreactedisopropyl bromide, keeping thepot; temperature ;b1QW 355 C., as thepressure is graduallyreduced' to about 275 millimeters. The residualmixture is then cooled .and .WfiShQd with 350 milliliters of waterfor-removalof sodiumbromide. The organic material remaininglamounts to:about 30.0 grams, and is crude isopropylmalonicester.

Sapanification of crude isopropylmalanic ester Sodium hydroxide (160grams) is di s solve d;in1 200 milliliters of methanol with stirring,theheat ofsolution causing the mixture to reflux. All of the crude -isopropylmalonic ester, described above, is addedwith vigorous stirring tothe refluxing sodium hydroxide solution during five to ten minutes. Thereaction is exothermic, causing brisk refluxthroughout,theadditiomperiod. During this time a thick slurry ofdisodium isopropylmalonate is formed. The mixture may be refluxed foraperiod of about one hour to insure complete saponification. The slurryis filtered with suction, and the resulting solid is Washed on thefilter with 500 milliliters of fresh methanol. The filter cake is driedat 110-120 C., giving about 295 grams of disodium isopropylmalonate. Theproduct is a fine powder, and is essentially free of color and odor.Over-all yields, based on diethyl malonate, average about 78 percent oftheory.

EXAMPLE II Preparation of sec-butylmalonic ester Starting with 110 gramsof sodium methylate, 340 grams of methanol, 320.3 grams of diethylmalonate, and 276.8 grams of sec-butyl bromide, sec-butylmalonic esteris prepared by the process described above for preparatron ofisopropylmalonic ester. The crude sec-butylmalonic ester obtained inthis way amounts to approximately 300 grams.

Saponification of crude sec-butylmalonic ester St arting with 160 gramsof sodium hydroxide, '1200 milliliters of methanol, and all of the crudesec-butylmalonrc ester, the saponification is run by the processdescribed above for isopropylmalonic ester. The sa- EXAMPLE III Disodiumallylmalonate F fty grams of diethyl allylmalonate (commerciallyavailable) were added to a refluxing solution of 23 grams of sodiumhydroxide in 200 milliliters of methyl alcohol during about fiveminutes. Saponification was rapid and exothermic. A thick slurry of thedisodium salt formed during the reaction period. The slurry was filteredwith suction, and the resulting solid was washed on the filter with 300milliliters of methyl alcohol. The

washed solid was dried at 110-120 C., giving 32.1 grams (68 percent oftheory) of disodium allylmalonate.

EXAMPLE IV Disodium phenylmalonate Disodium phenylmalonate One-half mole(118.2 grams) of diethyl phenylmalonate was added to a refluxingsolution of 45 grams of sodium hydroxide in 200 milliliters-of ethylalcohol during about five minutes. Saponification was rapid andexothermic. The resulting slurry was filtered with suction and the solidwas dried at 110-420 C.,v giving 79 grams (70 percent of theory) ofdisodium phenylmalonate.

EXAMPLE VI Disodium allylmalonate Forty-seven grams (0.235 mole) ofdiethylallylmalonate were added to a refluxing mixture of 22 grams ofsodium hydroxide and 200 milliliters of isopropyl alcool. The mixturewas refluxed for thirty minutes, during which-time a slurry formed. Thesolid was recovered by filtration with suction. The solid was dried at110-120 C., giving 26.3 grams (59 percent of theory) of disodiumallylmalonate.

EXAMPLE 'VlI .Disodium phenylmalonate one half mole (118.2 grams) ofdiethyl phenylmalonate was refluxed with a mixture of 45 grams of sodiumhydroxide and 200 milliliters of isopropyl alcohol. The resulting slurrywas filtered with suction and the solid 'was dried at 110l20 C., giving35 grams (31 percent of theory) of disodium phenylmalonate.

While the various examples in the foregoing have indicated yieldssomewhat lower than this result is in part due to the fact that a crudemonosubstitutcd malonic ester was used in the saponification process. Ithas been found the saponification reaction in fact goes to about 100%completion and any reduction in yields is in part due to the use ofcrudestarting materials, and the partial solubility of the sodium saltin the reaction medium.

While the foregoing examples have illustrated the saponification andrecovery of substantially pure disodium salts of monosubstituted malonicacids, it should be mentioned that small amounts of impurities that maybe contained therein are not sufficient to have any deleterious effectwhen these compounds are utilized as additive to smoking tobacco. Alsoany disodium salts that may not have precipitated and remain in solutionmay be recovered by reusing the filtrate as the medium in-a subsequentsaponification operation as is well known.

A may readily be seen the process of the present invention fulfills thestated objects in that there is provided thereby a method of saponifyingand recovering from said saponification mixture a disodium salt of amonosubstituted malonic acid in relatively pure form without thenecessity of separate andextended purification and isolation steps whichwere heretofore encountered in the processes generally known in theprior ,art.

The foregoing examples show that the best yields are obtained whenmethyl or ethyl alcohol is used as the saponification medium, althoughisopropyl alcohol is satisfactory. As indicated substantially anhydrousconditions are preferred but small amounts of water may be present.Generally the percent of water in the alcohol should not exceed 30% andpreferably should not exceed 20%, or otherwise the disodium salt becomestoo soluble and cannot be recovered by the simple procedure hereinoutlined.

While several particular embodiments of this invention are shown above,it will be understood, of course, that the invention is not to belimited thereto, since many modifications may be made, and it iscontemplated, therefore, by the appended claims, to cover any suchmodifications as fall within the true spirit and scope of thisinvention.

What is claimed is:

1. A process for preparing a solid disodium salt of a substitutedmalonic acid which comprises saponifying under reflux conditions :asubstituted malonic ester having the formula:

CO0R3 wherein R is a hydrocarbon radical having from 1 to 6 carbonatoms, and R and R are each lower alkyl groups, in an admixture of analkaline reacting sodium compound, a lower alkyl alcohol containing upto 3 carbon atoms, and up to about 30% by weight water based on saidlower alkyl alcohol whereby a major amount of said disodium salt isformed as a precipitate in the reaction mixture, and separating saidprecipitate from said mixture.

2. A process for preparing a solid disodium salt of a substitutedmalonic acid which comprises saponifying under reflux conditions asubstituted malonic ester having the formula:

wherein R is a hydrocarbon radical having from 1 to 6 carbon atoms and Rand R are each lower alkyl groups, in an admixture of sodium hydroxide,an alcohol containing up to 3 carbon atoms and up to about 30% by weightof water based on said alcohol whereby a major amount of said disodiumsalt is formed as a precipitate in the reaction mixture, and separatingsaid precipitate from said mixture.

3. A process for preparing a solid disodium salt of a substitutedmalonic acid which comprises saponifying under reflux conditions asubstituted malonic ester having the formula:

wherein R is a hydrocarbon radical having from 1 to 6 carbon atoms and Rand R are each lower alkyl groups, in an admixture of sodium hydroxide,methanol, and up 6 to 30% by weight of water based on methanol, wherebya major amount of said disodium salt is formed as a precipitate in thereaction mixture, and separating said precipitate from said mixture.

4. The process of claim 3 wherein said salt is separated by filtration.

5. A process for preparing a substantially pure disodium salt of asubstituted malonic acid which comprises saponifying under refluxconditions a lower alkyl substituted lower alkyl malonic ester havingthe formula:

wherein R isa hydrocarbon radical having from 1 to 6 carbon atoms and Rand R are each lower alkyl groups, in an admixture of sodium hydroxide,ethanol, and up to 30% by weight of water based on ethanol, whereby amajor amount of said disodium salt is formed as a precipitate in thereaction mixture, and separating said precipitate from said mixture.

6. A process for preparing a solid disodium salt of a. monosubstitutedmalonic acid which comprises saponifying under reflux conditions a loweralkyl substituted lower alkyl malonic ester having the formula:

wherein R is a hydrocarbon radical having from 1 to 6 carbon atoms and Rand R are each lower alkyl groups, in an admixture of sodium hydroxide,an alcohol selected from the group consisting of methanol, ethanol andisopropanol, and between about 0 and about 20 weight percent water basedon said alcohol, whereby a major amount of said disodium salt is formedas a precipitate in the reaction mixture, and separating saidprecipitate from said mixture.

7. The process of claim 6 wherein the disodium salt is separated byfiltration.

8. The process of claim 6 wherein R and R are each selected from thegroup consisting of ethyl and methyl.

9. A process for preparing a solid disodium salt of a. monosubstitutedmalonic acid which comprises contacting at an elevated temperature alower alkanol ester of a substituted malonic acid selected from thegroup consisting of lower alkyl, lower alkenyl and phenylmonosubstituted malonic acids with sodium hydroxide in an alcoholicsolution for a time sufliicient to saponify said ester, said alcohol insaid alcoholic solution containing from one to three carbon atoms andsaid solution containing less than 30% by weight of water, whereby amajor amount of said disodium salt is formed as a precipitate andthereafter separating said precipitate from the reaction mixture.

References Cited in the file of this patent Breslow: J.A.C.S. 66, pg.1287 (1944). Wagner et al.: Synthetic Organic Chemistry, pg. 417 (1953).

9. A PROCESS FOR PREPARING A SOLID DISODIUM SALT OF A MONOSUBSTITUTEDMALONIC ACID WHICH COMPRISES CONTACTING AT AN ELEVATED TEMPERATURE ALOWER ALKANOL ESTER OF A SUBSTITUTED MALONIC ACID SELECTED FORM THEGROUP CONSISTING OF LOWER ALKYL, LOWER ALKENYL AND PHENYLMONOSUBSTITUTED MALONIC ACIDS WITH SODIUM HYDROXIDE IN AN ALCOHOLICSOLUTION FOR A TIME SUFFICIENT TO SAPONIFY SAID ESTER, SAID ALCOHOL INSAID ALCOHOLIC SOLUTION CONTAINING FROM ONE TO THREE CARBON ATOMS ANDSAID SOLUTION CONTAINING LESS THAN 30% BY WEIGHT OF WATER, WHEREBY AMAJOR AMOUNT OF SAID DISODIUM SLAT IS FORMED AS A PRECIPITATE ANDTHEREAFTER SEPARATING SAID PRECIPITATE FROM THE REACTION MIXTURE.